Hum. Mutat. [JOURNAL]
Sun
200 papers
A Combined Transcriptomic and Machine Learning Study Reveals PAX8 as a Promising Diagnostic Biomarker in Endometriosis.
Zhu X, Zhong L, Xu Y … +3 more , Zou Y, Liu M, Tong X
Hum Mutat · 2026 · PMID 42006148 · Full text
BACKGROUND: Endometriosis (EM) is a chronic, estrogen-dependent disease that lacks reliable noninvasive diagnostic biomarkers. This study was aimed at evaluating the diagnostic value of PAX8 using integrated transcriptom...
BACKGROUND: Endometriosis (EM) is a chronic, estrogen-dependent disease that lacks reliable noninvasive diagnostic biomarkers. This study was aimed at evaluating the diagnostic value of PAX8 using integrated transcriptomic and machine learning analyses. METHODS: Transcriptomic data from the GSE141549 dataset were analyzed to identify differentially expressed genes (DEGs). Weighted gene coexpression network analysis (WGCNA), immune infiltration profiling, and functional enrichment (GO, KEGG, and GSEA) were conducted. Random forest (RF), support vector machine (SVM), and logistic regression (LR) models were trained and validated through five-fold cross-validation. RESULTS: A total of 887 DEGs were identified, among which PAX8 was significantly downregulated in ectopic tissues and identified as a key diagnostic feature by both RF and WGCNA. GSEA revealed that PAX8-related gene sets were enriched in biological processes such as cilium organization and wound healing, and KEGG analysis indicated involvement in calcium signaling, JAK-STAT signaling, and focal adhesion pathways. Immune infiltration analysis further supported an immunomodulatory role of PAX8.
A De Novo Mutation (c.2423A>G) in Causing MIRAGE Syndrome With Intrauterine Growth Retardation and Renal Hypoplasia in a Chinese Family.
Huang Y, Fu J, Gan Z … +3 more , Xiong F, Zhu H, Yang F
Hum Mutat · 2026 · PMID 42006147 · Full text
BACKGROUND AND AIMS: MIRAGE syndrome is an autosomal-dominant genetic disease primarily caused by a de novo mutation in the gene SAMD9 gene. This study is aimed at investigating the pathogenesis of MIRAGE syndrome throug...
BACKGROUND AND AIMS: MIRAGE syndrome is an autosomal-dominant genetic disease primarily caused by a de novo mutation in the gene SAMD9 gene. This study is aimed at investigating the pathogenesis of MIRAGE syndrome through a Chinese case exhibiting intrauterine growth retardation and renal hypoplasia. METHODS: We performed clinical exome sequencing to identify the pathogenic loci in the family. Further functional studies were conducted to understand the impact of the identified mutation. RESULTS: We identified a de novo mutation in SAMD9 that causes MIRAGE syndrome: c.2423A>G p.(Tyr808Cys). This mutation was associated with a novel phenotypic combination of intrauterine growth retardation and renal hypoplasia in a fetus. In vitro functional experiments demonstrated that the SAMD9 mutation reduced its levels of mRNA and protein. CONCLUSION: This study expands the pathogenic mutation spectrum of MIRAGE syndrome and provides new insights into its pathogenic mechanism. The identified mutation in SAMD9 provides a potential target for understanding and treating this complex disease.
SPP1 as a Critical Regulator of Cardiac Cell Reprogramming Following Myocardial Infarction Through Single-Cell Transcriptomic Analysis.
Wang R, Zhang M, Liu X … +2 more , Li Z, Chen X
Hum Mutat · 2026 · PMID 42006146 · Full text
BACKGROUND: Cardiovascular mortality remains predominantly driven by acute myocardial infarction (AMI), necessitating comprehensive elucidation of mechanisms governing cardiomyocyte reprogramming for therapeutic advancem...
BACKGROUND: Cardiovascular mortality remains predominantly driven by acute myocardial infarction (AMI), necessitating comprehensive elucidation of mechanisms governing cardiomyocyte reprogramming for therapeutic advancement. Characterizing molecular dynamics throughout cardiac repair processes presents substantial methodological challenges. METHODS: We employed a comprehensive analytical framework combining bulk and single-cell RNA sequencing datasets from AMI patients, utilizing 26 distinct machine learning algorithms to delineate critical regulatory gene signatures associated with cardiac repair. Gene prioritization was achieved through differential expression profiling coupled with consensus clustering methodologies. Functional validation experiments in H9c2 cardiomyoblast cellular models demonstrated that enhanced SPP1 expression is associated with augmented cellular viability and stimulated cardioprotective factor release, though these findings require validation in more physiologically relevant systems. RESULTS: Machine learning architectures successfully identified robust cardiomyocyte reprogramming signatures correlating with cardiac functional restoration. Consensus clustering analysis of 276 genes revealed two phenotypically distinct repair subtypes demonstrating divergent recovery trajectories ( < 0.001). Enhanced-recovery clusters exhibited upregulated proliferation markers alongside intensified angiogenic signaling cascades. SPP1 demonstrated exceptional predictive capacity (AUC = 0.896), with experimental validation suggesting its potential functional role in promoting cellular survival, proliferation, and secretion of cardioprotective mediators (VEGF, IGF-1; all < 0.05). CONCLUSION: This machine learning-driven approach successfully identified novel candidate prognostic biomarkers and potential therapeutic targets for cardiac repair interventions, substantially advancing mechanistic understanding of postinfarction cardiac remodeling processes. These findings generate testable hypotheses requiring validation in independent clinical cohorts and more physiologically relevant experimental systems.
A Pan-Cancer Atlas of TIPE2 Identifies Its Association With the Tumor Immune Microenvironment, Prognosis, and Immunotherapeutic Potential.
Cao H, Jia W, Yang H … +4 more , Zhang Y, Cao S, Zhou Y, Li Z
Hum Mutat · 2026 · PMID 41993135 · Full text
The tumor microenvironment (TME) plays a pivotal role in tumorigenesis, progression, and metastasis. Tumor necrosis factor alpha-induced protein 8-like 2 (TNFAIP8L2; TIPE2), a member of the TIPE family, is a key regulato...
The tumor microenvironment (TME) plays a pivotal role in tumorigenesis, progression, and metastasis. Tumor necrosis factor alpha-induced protein 8-like 2 (TNFAIP8L2; TIPE2), a member of the TIPE family, is a key regulator of immune homeostasis. In this study, we comprehensively characterized the pan-cancer landscape of TIPE2 and evaluated its potential significance for prognosis and immunotherapy-related stratification. Using multiomics data from public databases such as TCGA, GTEx, and HPA, we systematically analyzed TIPE2 expression patterns, genetic and epigenetic alterations, and their associations with clinical outcomes and immune characteristics across 33 cancer types. TIPE2 was found to be enriched in immune cells and frequently dysregulated in tumors compared with normal tissues. TIPE2 expression demonstrated a significant correlation with the infiltration of various immune cell populations across most cancers and exhibited strong associations with the expression of immune checkpoint genes. Alterations in TIPE2, along with aberrant methylation, were identified in a subset of tumors, indicating multilayered regulatory mechanisms. Gene set enrichment analysis further demonstrated that elevated TIPE2 expression is associated with immune-related pathways. Survival analyses demonstrated that TIPE2 expression was associated with overall survival and disease-free survival across multiple cancer types, exhibiting directionally heterogeneous effects depending on tumor context. Collectively, these findings identify TIPE2 as an immune-relevant biomarker candidate with prognostic significance across various cancers and warrant further mechanistic and clinical validation to elucidate its potential role in immunotherapy-based patient stratification.
c.392G>C Heterozygous Mutation Associates Primary Open-Angle Glaucoma in a Chinese Family.
Wang G, Guo Z, Ren J … +12 more , Zhang G, Tao H, Liu Y, Zheng S, Zhang X, Wang D, Zhao R, Cui H, Zhu S, Xu H, Duan S, Li H
Hum Mutat · 2026 · PMID 41993134 · Full text
Approximately 60% of glaucoma patients have a family history. Family-based studies indicate that relatives of glaucoma patients have a 10-fold higher risk of developing glaucoma compared to the control population. Geneti...
Approximately 60% of glaucoma patients have a family history. Family-based studies indicate that relatives of glaucoma patients have a 10-fold higher risk of developing glaucoma compared to the control population. Genetic mutations have been reported as potential contributing factors to pathogenesis of glaucoma. In this study, we reported a Chinese family that many members affected with primary open-angle glaucoma carried a c.392G>C heterozygous mutation. Western blotting results showed that this mutation decreased PAPPA2 protein level. Strikingly, we found PAPPA2 and its substrate IGFBP5 both expressed in human aqueous humor samples, and PAPPA2 levels significantly decreased in the POAG group accompanied with IGFBP5 levels increased in the POAG group. We also demonstrated that PAPPA2 cleaved IGFBP5 in vitro. We found that overexpressed IGFBP5 increased many fibrosis-related gene expression through mRNA sequencing, western blotting, and immunofluorescence staining assays in primary human trabecular meshwork cells (HTMCs). More importantly, we found an inadequate dose of Pappa2 caused POAG-like phenotypes in the mouse model. So, we proved the vital function of the eye local PAPPA2-IGFBP5 axis in regulating extracellular matrix homeostasis and contributing to trabecular meshwork fibrosis and pathogenesis of POAG.
Shuangshen Granule Regulates Tumor Cell Exosomes Through MIF-miR-34a-KLF4 Pathway and Affects Macrophage Polarization Against Lung Cancer.
Qi R, Li Y, He Z … +9 more , Zhao Y, Huang Q, Liu Y, Hou Y, Shi Z, Hua B, Pang B, Zhang Y, Guo Q
Hum Mutat · 2026 · PMID 41993133 · Full text
UNLABELLED: The incidence and mortality of lung cancer are among the highest in the world, involving a variety of complex pathological mechanisms and processes. Previous studies have demonstrated that the tumor immunosup...
UNLABELLED: The incidence and mortality of lung cancer are among the highest in the world, involving a variety of complex pathological mechanisms and processes. Previous studies have demonstrated that the tumor immunosuppressive microenvironment (TIME) plays a key role in tumor progression, promoting tumor invasion and metastasis and leading to resistance to therapy. Tumor-associated macrophages (TAMs) are important cell components in TIME, and their phenotypes affect the prognosis of tumors. Tumor-derived exosomes carrying specific information as a medium of crosstalk between macrophages and tumor cells are considered to be an underexplored information transfer medium affecting tumor progression and tumor microenvironment remodeling. In the previous study, we found that Shuangshen granule (SSG) can reduce the formation of lung tumors in mouse models of spontaneous lung cancer, but the specific mechanism of SSG inhibiting lung cancer has not been solved. Starting from the exosomes of tumor cells, we established the M1-like TAMs overexpression mouse lung cancer transplantation tumor model and constructed MIF Lewis stable transfection cell line and shMIF Lewis stable transfection cell line to analyze the specific molecular biological mechanism of SSG inhibiting lung cancer. The experimental results showed that SSG significantly reduced the volume and mass of Lewis lung cancer xenografts in mice, and its inhibitory effect on Lewis lung cancer was related to the increase in the proportion of M1-like TAMs. Flow cytometry and western blot revealed that SSG can increase the proportion of CD8 central memory T cells, reduce the proportion of CD8 effector memory T cells, reduce the proportion of CD4CD25Foxp3 Treg cells, and play a role in regulating the tumor microenvironment. In vitro experiments further showed that SSG drug-containing serum could inhibit the expression of MIF protein and RNA in MIF Lewis cells and increase the expression of miR-34a in MIF Lewis cell exosomes. Interestingly, we also found that MIF Lewis cell-derived exosomes after SSG-containing serum intervention can reverse the increase in the proportion of M2-like TAMs and increase the proportion of M1-like TAMs. Subsequent gene modification experiments showed that MIF Lewis cell exosomes can increase the expression of the KLF4 gene in macrophages in vitro. In conclusion, our study revealed that SSG can regulate the polarization of TAMs through lung cancer cell-derived exosomes, and its mechanism is related to the MIF-miR-34a-KLF4 pathway. SUMMARY: •SSG can inhibit the proliferation of lung cancer, which is related to the antitumor mechanism involving macrophages.•The poor prognosis of lung cancer caused by macrophage migration inhibitory factor (MIF) is related to the TAM phenotype, and SSG can inhibit lung cancer by inhibiting MIF.•SSG regulates the tumor cell MIF-MiR-34a exosome pathway and regulates the polarization and function of TAMs.
Targeting LY6E Inhibits Neuroblastoma Progression and Suppresses M2 Macrophage Polarization.
Li L, Zeng Y, Zhang Q … +4 more , Zhuang G, Liu Y, Wang X, Wang Y
Hum Mutat · 2026 · PMID 41993132 · Full text
Neuroblastoma is a pediatric malignancy characterized by significant clinical heterogeneity. Although MYCN amplification is a well-established marker of high-risk disease, its interplay with the tumor immune microenviron...
Neuroblastoma is a pediatric malignancy characterized by significant clinical heterogeneity. Although MYCN amplification is a well-established marker of high-risk disease, its interplay with the tumor immune microenvironment-particularly tumor-associated macrophages (TAMs)-remains poorly understood. In this study, we developed an integrated gene signature incorporating genes associated with both MYCN amplification status and TAM infiltration, leading to the identification of 16 differentially expressed genes implicated in both biological processes. Six of these genes (CMBL, LY6E, KLRB1, CTSH, CD3D, and PTGDS) were utilized to construct a risk-scoring model that effectively stratified neuroblastoma patients into high- and low-risk groups with significantly distinct clinical outcomes ( < 0.001). Notably, LY6E emerged as the most prognostically significant gene within the signature. More importantly, we revealed that LY6E modulates M2-type macrophage polarization in neuroblastoma for the first time, suggesting a novel mechanism through which it may contribute to shaping an immunosuppressive tumor microenvironment.
Mutations With Dominant-Negative Effect in Infantile Hypophosphatasia Monozygotic Twins.
Hao L, Huang N, Tao Y … +5 more , Li H, Zhuang J, Li X, Hao Z, Zhao F
Hum Mutat · 2026 · PMID 41993131 · Full text
BACKGROUND AND AIMS: Hypophosphatasia (HPP) is a rare inborn error of metabolism caused by gene mutations, resulting in deficient tissue-nonspecific alkaline phosphatase (ALP) activity. We investigated genotype-phenotyp...
BACKGROUND AND AIMS: Hypophosphatasia (HPP) is a rare inborn error of metabolism caused by gene mutations, resulting in deficient tissue-nonspecific alkaline phosphatase (ALP) activity. We investigated genotype-phenotype correlations in a monozygotic female twin pair with infantile HPP. METHODS: Peripheral blood samples were collected from two female twins with HPP and their family members. Genomic DNA was extracted, and variations were detected using whole exome sequencing. Zygosity was confirmed via KING 2.3.1 software. Pathogenic variants were validated using Sanger sequencing, mutation analyses, and bioinformatics. RESULTS: The twins presented with bulging anterior fontanel at 3 months of age. At 6 months, serum ALP levels decreased, and skeletal dysplasia, hypercalcemia, and nephrocalcinosis developed. One twin died of pneumonia at 11 months; the other remained alive beyond 15 months. Monochorionic diamniotic placentation and a twin pair kinship coefficient (0.4879) confirmed monozygosity. Exome sequencing revealed that the twins carried compound heterozygous mutations c.299C>T (p.Thr100Met) and c.1271T>C (p.Val424Ala). The maternally inherited allele c.1271T>C, which was suspected to be pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines, was reported in a homozygous Chinese adult with HPP. The paternally inherited allele c.299C>T was rated as pathogenic by ACMG. In vitro, c.299C>T-related mutants exhibited reduced residual ALP activity owing to a dominant-negative effect. Analysis of c.299C>T-related mutations in the Gene Variant Database revealed statistically significant differences in a dominant-negative effect and lower residual ALP activity of allelic mutants in early-onset versus late-onset HPP ( < 0.05). The dominant-negative effect correlated positively with residual ALP activity ( = 0.889, < 0.05). CONCLUSION: Compound heterozygous mutations c.299C>T (p.Thr100Met) and c.1271T>C (p.Val424Ala) were causative factors of infantile HPP in the monozygotic twins, providing insights into how dominant-negative effects influence HPP severity.
Genomic Structural Equation Modeling Provides an Initial View of the Genetic Architecture Related to Type 1 Gaucher Disease.
Ren S, Du M, Liu J … +3 more , Li B, Liu J, Lang X
Hum Mutat · 2026 · PMID 41993130 · Full text
The genetic architecture underlying traits associated with Type 1 Gaucher disease (GD1) remains insufficiently explored. We integrated genomic structural equation modeling and multiple post-genome-wide association study...
The genetic architecture underlying traits associated with Type 1 Gaucher disease (GD1) remains insufficiently explored. We integrated genomic structural equation modeling and multiple post-genome-wide association study (GWAS) methodologies to prioritize candidate SNPs associated with GD1-related variation, identifying 15 loci with strong statistical support. Subsequently, diverse transcriptome-wide association approaches were employed to pinpoint susceptibility gene signals strongly correlated with GD1. For selected candidate genes, we explored the potential structural consequences of missense variants using integrated structure prediction, molecular dynamics simulations, and AI-based thermodynamic stability analyses. These analyses suggested that the mutations may alter protein structure and dynamics, with possible consequences for protein stability and biological function. Next, we screened a large set of publicly available traits to identify GD1-related factors and biomarkers with potential relevance. Finally, a summary data-based polygenic risk score (PRS) was utilized to examine risk associations between 22 autosomes and GD1. Collectively, by modeling a GD1-related phenotype without direct prior measurement, this study provides an initial overview of the shared genetic architecture associated with GD1.
Panomics Integration via Machine Learning Prioritizes TAF1D as a Therapeutic Vulnerability in Lung Adenocarcinoma.
Ding L, Xu Q, Liu D … +6 more , Wu J, Cai X, Xu F, Ma S, Wang H, Shi Y
Hum Mutat · 2026 · PMID 41969615 · Full text
Lung adenocarcinoma (LUAD) is a leading cause of cancer mortality, necessitating the identification of robust biomarkers and a deeper understanding of its molecular underpinnings. This study is aimed at screening for pot...
Lung adenocarcinoma (LUAD) is a leading cause of cancer mortality, necessitating the identification of robust biomarkers and a deeper understanding of its molecular underpinnings. This study is aimed at screening for potential LUAD biomarkers and characterizing their biological functions. Using an integrative computational framework, we combined multitranscriptomic data analysis with three machine learning algorithms (LASSO, SVM-RFE, and random forest) to identify a consensus seven-gene signature (TTC13, TAF1D, ZNF587, PRPF3, LINC01355, TARBP1, and CCNL2). A classifier based on this signature achieved exceptional diagnostic accuracy (AUC = 0.972), with TAF1D identified as the most influential predictor via SHAP analysis. TAF1D was significantly upregulated in tumors, correlated with an immunosuppressive microenvironment, and promoted cancer cell proliferation by regulating cell cycle and immune-related pathways. Critically, TAF1D exhibited significant spatial heterogeneity in expression across different samples and tissue regions, suggesting it may exert region-specific biological functions within the tumor. In conclusion, our work defines a validated gene signature for LUAD, nominating TAF1D as a key oncogenic driver and promising candidate for diagnostic and therapeutic development.
Genome-Wide Cross-Trait Analysis Dissects the Shared Genetic Architecture Between Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease.
Zhu Z, Li H, Wang X … +2 more , Chen X, Cheng L
Hum Mutat · 2026 · PMID 41969614 · Full text
The observational studies confirmed the high prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with Type 2 diabetes mellitus (T2DM), but whether this reflects a shared genetic eti...
The observational studies confirmed the high prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in patients with Type 2 diabetes mellitus (T2DM), but whether this reflects a shared genetic etiology and exists underlying causal relationships remains unknown. Here, we utilized the largest scale cross-trait analysis from genome-wide association studies (GWASs) to investigate the shared genetic architecture and found a significant genetic correlation between T2DM and MASLD. Subsequently, we identified 581 shared risk single-nucleotide polymorphisms (SNPs) and observed consistent patterns of tissue-specific heritability enrichment in embryonic stem cells, stomach, kidney, large and small intestine, and pancreas. Of the six highly shared risk SNPs (rs7203132, rs11642015, rs58542926, rs6857, rs10404726, and rs738408), we further systematically performed regional and functional analysis. Using Mendelian randomization (MR), we discovered significant evidence for a positive causal effect with no reverse causality of T2DM on MASLD and further explained what causes causality to occur. Finally, we used an orthogonal strategy to provide genetic evidence, highlighting 11 possible comorbidity targets, most of which are located on Chromosomes 19 or 22 with five on 19p13.11, such as NCAN, MAU2, GATAD2A, TM6SF2, and GMIP. Our study sheds insights into the informed biology of comorbidity and reveals their shared genetic factors and potential drug targets.
Engineering of the Melanoma Inhibitor of Apoptosis (ML-IAP) Anticancer Peptide Through Comprehensive In Silico Approaches.
Al-Madhagi HA, Shahab M, Guojun Z … +5 more , Al-Madhagy G, Bourhia M, Shazly GA, Dauelbait M, Huang Z
Hum Mutat · 2026 · PMID 41969613 · Full text
BACKGROUND AND AIMS: Melanoma represents the most malignant type of skin cancer. It is estimated that approximately 100,000 new cases of melanoma were diagnosed in 2022, resulting in over 7600 deaths in the United States...
BACKGROUND AND AIMS: Melanoma represents the most malignant type of skin cancer. It is estimated that approximately 100,000 new cases of melanoma were diagnosed in 2022, resulting in over 7600 deaths in the United States alone. Recently, anticancer peptides (ACPs) have emerged as novel therapeutic agents for cancer, offering higher potency, biocompatibility, and fewer adverse reactions in host cells. One of the druggable targets of melanoma is the melanoma inhibitor of apoptosis (ML-IAP), conventionally inhibited by the nonapeptide AVPIAQKSE. The current study is aimed at enhancing both the binding affinity and safety profile of this peptide through in silico peptide engineering. METHODS: Initially, the 3D structure of the protein was downloaded from the Protein Data Bank (PDB) (ID: 1OXQ) and prepared. The hotspot residues at the interface were detected using Discovery Studio Client 2021. Afterwards, saturation mutagenesis was conducted to discover the best potential amino acid substitutions with a positive impact on the binding affinity. The lead candidates were docked to the receptor via HPEPDOCK 2. Additionally, the safety profile was assessed using the ToxIBTL and AllerCatPro 2 servers. Finally, molecular dynamics simulations and principal component analysis were performed to check the stability of the best complexes. RESULTS: HVPIAQKSE, WVPWAQKSE, and HVPWAQKSE were the best mutants that could be superior to the original peptide in terms of binding affinity as well as safety profile. MD results confirmed the stability, flexibility, reduced local motions, conformational changes, and more compact structure upon binding the receptor for 200 ns, which deserve in vitro validation as a better melanoma ACP therapeutic option. CONCLUSION: These variants displayed increased flexibility, reduced conformational alterations and local motions, and a more compact configuration, suggesting greater stability compared with the reference peptide.
Development of a Multiplex Amplification System Using Oxford Nanopore Sequencing for STRs and InDels.
Han W, Zhang Q, Zhang X … +5 more , Feng M, Xu H, Geng X, Wang Y, Zhou Z
Hum Mutat · 2026 · PMID 41969612 · Full text
Nanopore sequencing has emerged as a promising technology due to its real-time data acquisition, portability, and high throughput. However, the genotyping capabilities of the latest flow cell, R10.4.1, for short tandem r...
Nanopore sequencing has emerged as a promising technology due to its real-time data acquisition, portability, and high throughput. However, the genotyping capabilities of the latest flow cell, R10.4.1, for short tandem repeats (STRs) remain insufficiently validated, and its accuracy in typing insertions or deletions (InDels) in earlier versions has been rarely investigated. To bridge these gaps, we developed the NanoID panel, a multiplex amplification system incorporating 29 autosomal STRs, 29 Y-chromosome STRs, 61 autosomal InDels, 2 Y-chromosome InDels, and amelogenin. We conducted genotyping on 112 unrelated individual samples and screened 114 loci with 100% accuracy. Subsequently, we evaluated these 114 loci for reproducibility, sensitivity, kinship inference, and species specificity. All loci were consistently and accurately genotyped across triplicate experiments. NanoID achieved an accuracy rate exceeding 99.12% (based on the 2-out-of-3 rule) when the DNA input was ≥ 50 pg. The combined power of discrimination and the cumulative probability of exclusion were 1 - 7.990 × 10 and 1 - 2.299 × 10, respectively. For full-sibling kinship testing, the sensitivity, specificity, and accuracy reached 100% at likelihood ratio (LR) cutoff values of 0.0001 and 10000. Nonhuman samples were clearly distinguishable from human samples. These findings strongly support the NanoID system's effectiveness for individual identification and full-sibling kinship analysis using nanopore sequencing.
Integrative Multiomics and Single-Cell Analyses Identify FKBP10 as a Predictor of Radiotherapy Outcome in Colorectal Cancer.
Xinmo F, Minghua B, Xu Q … +5 more , Weiwei L, Lin W, Qinghui D, Rui W, Ji Z
Hum Mutat · 2026 · PMID 41969611 · Full text
BACKGROUND: Radiotherapy resistance limits colorectal cancer (CRC) treatment efficacy, with only 15%-20% of patients achieving a complete response. Validated biomarkers predicting treatment response and serving as therap...
BACKGROUND: Radiotherapy resistance limits colorectal cancer (CRC) treatment efficacy, with only 15%-20% of patients achieving a complete response. Validated biomarkers predicting treatment response and serving as therapeutic targets are critically needed. METHODS: We performed integrative multiomics analysis of 200 CRC patients (GSE87211) with independent validation in 58 patients (GSE46862). Single-cell RNA sequencing of 63,689 cells (GSE132465) determined cell-type-specific expression. Functional validation was conducted in radiotherapy-resistant CRC cell lines through loss-of-function experiments including proliferation, migration/invasion, and radiosensitivity assays. RESULTS: FKBP10 emerged as the only gene achieving statistical significance in both discovery (log2FC = 0.74, = 0.0007) and validation (log2FC = 0.52, = 0.032) cohorts among 48 radioresistance-associated genes. Single-cell profiling revealed that FKBP10 was predominantly expressed in cancer-associated fibroblasts (CAFs, 51.5% of stromal cells), implicating CAF-mediated stromal remodeling in resistance. FKBP10 knockdown significantly inhibited proliferation, colony formation (35%-40% reduction), migration (30%), and invasion (50%), while markedly enhancing radiosensitivity through increased DNA damage (H2AX foci increased twofold, < 0.01) and strand breaks (comet tail DNA: 22% → 43%, < 0.01). CONCLUSIONS: This multiomics study establishes FKBP10 as a robust CAF-derived biomarker and functional therapeutic target for radiotherapy resistance in CRC, providing a foundation for developing FKBP10-targeted combination strategies for precision cancer treatment.
Variations in DNA Repair Genes and Intratumoral Genetic Heterogeneity in Temozolomide-Resistant Glioblastoma.
Chen W, Li C, Liu Y … +1 more , Huang H
Hum Mutat · 2026 · PMID 41969610 · Full text
BACKGROUND: Glioblastoma (GBM) is the most prevalent primary brain tumor. Despite extensive investigations, GBM's resistance to the first-line drug temozolomide (TMZ) remains a major challenge in clinical management. Thi...
BACKGROUND: Glioblastoma (GBM) is the most prevalent primary brain tumor. Despite extensive investigations, GBM's resistance to the first-line drug temozolomide (TMZ) remains a major challenge in clinical management. This study explores the molecular mechanisms underlying TMZ resistance in GBM, emphasizing the roles of DNA repair gene polymorphisms and intratumoral genetic heterogeneity. METHODS: In this study, we collected 10 matched pairs of GBM surgical samples, including tumor tissues from the first and second surgeries, and proceeded with RNA-Seq and Exome-Seq. We performed pathway enrichment analysis and functional assays for key genetic variations in the DNA repair pathway to establish a mechanistic relationship between genetic changes and drug resistance. Sanger sequencing validated somatic variations before and after chemotherapy, and we analyzed changes in gene expression associated with DNA repair. The methylation status of the promoter region of the MGMT gene was analyzed, in addition to the effect of DNA repair genes on TMZ sensitivity in cells. RESULTS: This study identified 20 novel somatic mutations that uniquely occurred in pre-TMZ and post-TMZ chemotherapy samples and were significantly related to DNA repair pathways (including base excision repair [BER] and nucleotide excision repair [NER]). Functional validation experiments confirmed that the alterations in the expressed variants had disrupted important repair mechanisms related to the survival of tumor cells. Notably, differential dysregulation of the NER and BER pathways (upregulated NER and inactivated BER) was observed in recurrent tumors, serving as a compensatory mechanism for TMZ resistance. Methylation of the MGMT gene promoter region has been linked to TMZ resistance, while intratumoral genetic heterogeneity might increase the chance of resistance. Importantly, our observations point toward an evolutionary event following TMZ treatment that incorporates selective pressures for repair-deficient clones, resulting in a more aggressive fate for GBM. Cellular studies showed that the proliferation and migration ability of U87 cells were significantly elevated after the knockdown of XAB2, PNKP, and OGG1. CONCLUSION: This study represents the first comprehensive characterization of TMZ resistance in GBM based on integrated genetic, epigenetic, and functional validation approaches. In GBM, mechanisms of TMZ resistance are elucidated, with the interplay between the NER and BER pathways (compensatory regulation) being a key mechanism, alongside variations in DNA repair genes and intratumoral genetic heterogeneity. These findings highlight the importance of targeting the crosstalk between NER and BER pathways for GBM therapy, emphasizing the necessity of personalized treatment strategies and suggesting possible biomarkers for patient stratification by resistance profiles. Overall, these findings provide new avenues for developing personalized treatment strategies for GBM and can contribute to improving the prognosis of GBM patients.
Assessing Allele Frequency Information: A Study of Variant Curation Expert Panel Guidelines.
Wang X, Zhang T, Qin Y … +4 more , Zou Y, Luo H, Li H, Song J
Hum Mutat · 2026 · PMID 41969609 · Full text
PURPOSE: The 2015 guidelines recommend using a large, diverse, and race-matched reference database. However, defining expectations in this context is subjective due to factors like genetic diversity and penetrance. ClinG...
PURPOSE: The 2015 guidelines recommend using a large, diverse, and race-matched reference database. However, defining expectations in this context is subjective due to factors like genetic diversity and penetrance. ClinGen forms VCEPs to provide gene-specific interpretations of ACMG/AMP guidelines, including population information. Our study evaluates VCEP guidelines on allele frequency information. METHODS: We analyzed genetic codes in databases to determine the frequency and potential pathogenicity of variants among 39 VCEPs, considering factors like allele frequency thresholds and disease prevalence. RESULTS: Our analysis found a variety of approved cutoffs among VCEPs, showing diverse disease mechanisms. We also noted variability in methods used to establish cutoffs and inconsistencies in parameters deemed necessary for approved thresholds. CONCLUSIONS: Understanding thresholds requires knowledge of genetics and diseases. VCEP guidelines on allele frequency evidence can help curators identify recommended thresholds. However, more guidance is needed for consistency in population evidence utilization.
Use of Single-Cell Data and scPagwas Analysis to Identify T Cell Subsets and Construct a Prognostic Model for Clear Cell Renal Cell Carcinoma.
Yi X, Jia Z, Wu J … +5 more , Wang S, Yu Y, Kong Y, He X, Huang Y
Hum Mutat · 2026 · PMID 41960370 · Full text
BACKGROUND: Clear cell renal cell carcinoma (KIRC), the most prevalent pathological renal cell carcinoma (RCC) subtype, makes up approximately 75%-84% of total cases. KIRC is characterized by high heterogeneity, high met...
BACKGROUND: Clear cell renal cell carcinoma (KIRC), the most prevalent pathological renal cell carcinoma (RCC) subtype, makes up approximately 75%-84% of total cases. KIRC is characterized by high heterogeneity, high metastasis rates, and a poor prognosis. Its incidence rate has continued to rise in recent years. We sought to construct new prognostic models to optimize treatment decisions, improve clinical benefits, and explore potential therapeutic targets. METHODS: This study integrated various omics data including single-cell RNA seq (GSE171306), TCGA-KIRC, GWAS, and validation datasets (GSE29609 and E-MTAB-1980). The scPagwas algorithm combines GWAS with scRNA-seq to identify immune subgroups with high feature correlation. Key genes are identified through the combination of weighted correlation network analysis (WGCNA) with differentially expressed genes (DEGs). We built a clinical prognostic model by using machine learning algorithms and validated it through survival rate and receiver operating characteristic (ROC) analysis. We used cancer drug sensitivity genomics data to analyze drug sensitivity and performed molecular docking to identify potential therapeutic drugs. RESULTS: Using single-cell RNA seq data, we identified T cell subsets as characteristic cell subsets in KIRC through scPagwas analysis. In single-cell analysis, key genes in T cell subsets and genes with PCC values > 0.05 were combined with the core genes in DEGs and WGCNA modules, thus yielding 86 intersecting genes. These genes were significantly enriched in immune-related pathways. We established a clinical prognostic model containing seven risk genes. Low-risk patients exhibited substantial survival advantages. Time-dependent ROC analysis indicated the prognostic model's excellent clinical predictive value. Functional enrichment, immune infiltration, and somatic mutation analyses highlighted different biological mechanisms among risk populations. The SHAP values of the XGBoost and LightGBM machine learning algorithms indicated DOCK8 as a potential biomarker. Drug prediction and molecular docking predicted five potential drugs targeting DOCK8 (finasteride, nocodazole, palonosetron, pifithrin alpha, and topiramate). CONCLUSION: Our systematic analysis of the immune microenvironment, key genes, and prognosis of KIRC highlighted the critical roles of T cell subsets. We additionally established an effective clinical prognostic model. Our findings provide new insights and potential targets for the precise diagnosis and targeted KIRC therapy.
ERMP1 Exerts Tumor-Suppressive Functions in KIRC by Inhibiting PI3K/AKT Signaling and Remodeling the Immune Microenvironment: A Pan-Cancer Analysis.
Liu Z, Shan J, Yang T … +3 more , Zhang Q, Ma L, Yang F
Hum Mutat · 2026 · PMID 41960369 · Full text
BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is an aggressive malignancy with limited therapeutic options, highlighting the need for novel biomarkers and therapeutic targets. Although endoplasmic reticulum metall...
BACKGROUND: Kidney renal clear cell carcinoma (KIRC) is an aggressive malignancy with limited therapeutic options, highlighting the need for novel biomarkers and therapeutic targets. Although endoplasmic reticulum metallopeptidase 1 (ERMP1) has been implicated in cancer progression, its specific role, clinical significance, and underlying mechanisms in KIRC remain poorly defined. METHODS: We integrated data from the TCGA, GTEx, and GEO databases to conduct a pan-cancer analysis, aiming to systematically evaluate the expression patterns, genetic alterations, and prognostic value of ERMP1. Single-cell transcriptomic data were utilized to decipher its cell-type-specific expression within the tumor immune microenvironment. By establishing ERMP1 overexpression models in KIRC cell lines (Caki-1 and A498), we assessed its impact on malignant phenotypes using CCK-8, colony formation, transwell, and wound healing assays. The underlying mechanisms were further investigated via Western blotting. Finally, by establishing a xenograft tumor model in vivo, we evaluated the inhibitory effect of ERMP1 on tumor growth of KIRC in vivo. RESULTS: The prognostic value of ERMP1 exhibits cancer type-specificity. In KIRC, its high expression serves as an independent marker for favorable prognosis and is negatively correlated with advanced pathological features. Single-cell analysis revealed that ERMP1 is enriched in regulatory T cells and proliferative exhausted T cells. Its high expression is closely associated with an immunologically activated tumor microenvironment, characterized by upregulation of immunostimulatory factors and chemokines, alongside increased lymphocyte infiltration. Functionally, ERMP1 overexpression significantly suppressed the proliferation, migration, invasion, and clonogenic ability of KIRC cells. Mechanistically, ERMP1 inhibits the PI3K/AKT signaling pathway, impedes epithelial-mesenchymal transition (manifested as E-cadherin upregulation and N-cadherin downregulation), and reduces the expression of invasion-related proteins (MMP2 and MMP9) and cell cycle-related proteins (Cyclin D1 and CDK4). In vivo xenograft tumor assays confirmed that ERMP1 overexpression could significantly inhibit tumor growth. CONCLUSION: This study confirms that ERMP1 exhibits significant potential in tumorigenesis, diagnosis, prognosis, and regulation of the tumor microenvironment (TME). In KIRC, ERMP1 may exert tumor-suppressive effects by inhibiting the PI3K/AKT signaling pathway and regulating immune responses, thus representing a potential prognostic biomarker and therapeutic target.
Cellular Functional Analyses of Variants Reveal New Insights Into Genotype-Phenotype Correlations in Neurodevelopmental Disorders Among Male and Female Patients.
Faraj R, Farrugia A, Hurst ACE … +9 more , Conan P, Martin J, Schalk A, Redon S, Dubos A, Gras M, Curie A, Voisset C, Friocourt G
Hum Mutat · 2026 · PMID 41960368 · Full text
Neurodevelopmental disorders (NDDs) encompass a wide range of conditions often linked to genetic causes, with mutations in the X-linked gene representing a recurrent contributor. encodes a transcription factor critical...
Neurodevelopmental disorders (NDDs) encompass a wide range of conditions often linked to genetic causes, with mutations in the X-linked gene representing a recurrent contributor. encodes a transcription factor critical for GABAergic neuron development and functioning, regulating the expression of key neurodevelopmental target genes. Variants in result in a wide clinical spectrum, ranging from asymptomatic female carriers to severe developmental syndromes in both sexes. This study investigates the functional impact of 16 variants, including known pathogenic, likely pathogenic, and novel de novo variants, some associated with atypical presentations such as sudden infant death. Using transient expression in N2a neuroblastoma cells, we employed a comprehensive functional approach-including luciferase reporter assays, Western blotting, immunofluorescence, and RT-qPCR-to assess protein expression levels, subcellular localization, their interaction with known corepressors (TLE1 and CtBP1), and their transcriptional activity on selected -known targets. Our results demonstrate that all tested variants disrupt normal transcriptional function, with several also altering protein localization or expression. Remarkably, a subset of variants exhibited dominant-negative effects, offering a compelling explanation for unexpectedly severe phenotypes in female patients, likely exacerbated by skewed X-inactivation and other modifying factors. By integrating experimental data with a literature-based review of published variants, we provide refined genotype-phenotype correlations, highlighting the importance of mutation type, positional context within key functional domains, and patient sex. Altogether, this study advances our understanding of the molecular mechanisms driving -related NDDs, emphasizing the importance of functional testing for accurate variant interpretation and paving the way toward informed genetic counseling and potential therapeutic development.
SIRT3 Regulates HMGCS2 Deacetylation and Influences Cholangiocarcinoma Progression via the Metabolism of Ketone Bodies.
Liu S, You X, Wang D … +10 more , Wang X, Yang Y, Chen F, Zheng J, Qi F, Sun W, Peng W, Xi J, Lu Z, Zhang D
Hum Mutat · 2026 · PMID 41960367 · Full text
Cholangiocarcinoma (CCA) is a highly aggressive malignancy. 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a mitochondrial enzyme involved in ketogenesis, has been linked to tumor progression, but its role in CCA re...
Cholangiocarcinoma (CCA) is a highly aggressive malignancy. 3-Hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), a mitochondrial enzyme involved in ketogenesis, has been linked to tumor progression, but its role in CCA remains unclear. HMGCS2 expression in CCA tissues was analyzed using TCGA data and immunoblotting (IB). Functional assays were performed in CCA cell lines (HuCCT-1 and RBE) and an in vivo xenograft model. Metabolomics explored HMGCS2-mediated metabolic changes. SIRT3-HMGCS2 interactions were examined via molecular docking, IF, CO-IP, GST pull-down, and CHX assays, with mutational analysis identifying interaction sites. IHC assessed clinical samples. HMGCS2 was downregulated in CCA. Overexpression inhibited proliferation and invasion, while knockdown promoted these effects, consistent in vitro and in vivo. Metabolomics showed HMGCS2 enhanced ketone body synthesis, and exogenous ketone bodies mimicked its antitumor effects. SIRT3 deacetylated HMGCS2 at K310 (with plasmid mutation assay), and low HMGCS2/SIRT3 expression correlated with poor patient survival. SIRT3-mediated deacetylation of HMGCS2 promotes ketone body synthesis, suppressing CCA progression. HMGCS2 is a potential therapeutic target for CCA.
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